Aging in the female rat is associated with a gradual decline in regular estrous cycles, and the cessation of regular cyclicity is preceded by significant decreases in the magnitude of LH surge and progesterone secretion on proestrus. During the estrous cycle, the cyclic increases in estradiol and testosterone secretion also occur earlier and in greater magnitude in middle-aged female rats which soon cease to display regular cycles. Our recent studies have demonstrated that repetitive increases in circulating progesterone by Silastic implants or through caging with fertile males significantly maintain normal gonadotropin secretion and decelerate the loss of regular cyclicity in aging females. These data suggest that prolonged exposure to high levels of estradiol may render the neuroendocrine system progressively less responsive to the stimulatory feedback actions of ovarian steroids. There is evidence to indicate that progesterone in steroid sensitive cells can effectively decrease the biological actions of estradiol. This grant proposal has outlined systematic approaches to determine whether the positive feedback of gonadotropin response to estradiol is progressively decreased in aging female rats through the transition from a regular cyclic to an irregular cyclic state, and to see if this functional alteration is due to a decrease in hypothalamic GnRH release, a reduced pituitary responsiveness to GnRH, or both. Since progesterone implants decelerate the loss of regular cycles in aging females, studies are proposed to determine whether progesterone maintains a normal neuroendocrine responsiveness to ovarian estradiol stimulation. In vitro experiments on hypothalamic perifusion will be performed to determine if high levels of estradiol inhibit hypothalamic GnRH release and progesterone prevents the deleterious effect of estradiol on GnRH release. We propose that alterations in estradiol and progesterone secretion in aging female rats gradually decrease the hypothalamic GnRH responsiveness to the stimulatory feedback actions of ovarian steroids, thereby inhibiting the positive feedback mechanism and the regular ovulatory function.